Panic Disorder (PD) is a chronic and disabling condition that afflicts approximately 6 million people annually. Recent studies report that PD incidence is almost double in veterans. PD has high comorbidity with PTSD and afflicted individuals report higher rates of disability, cost of treatment and treatment resistance. Thus, studies on the search for novel, effective interventions and preclinical models relevant to PD-PTSD comorbidity are of high relevance. Neurobiological models of panic propose a central homeostatically-driven alarm system coupled with a supersensitive fear/anxiety system. Consistently, panic attacks can be triggered in individuals with PD and PTSD following challenges such as carbon dioxide (CO2) inhalation and sodium lactate, suggesting homeostatic imbalance in pH, specifically acidosis. Mechanisms for translation of acidosis to fear/panic are critical to the pathophysiology of panic and may lead to specific therapeutic treatment of panic attacks in veterans. Recently, our group has shown a role of microglial acid-sensing receptor T-cell death associated gene-8 (TDAG8), and ensuing microglial inflammation in CO2-evoked fear and panic responses. Microglial acid-sensing and inflammation may provide a core mechanism to explain the basis of panic, especially following trauma associated with PTSD This Merit Review application proposes to investigate microglial mechanisms in a rodent model of PTSD (single prolonged stress, SPS) expressing panic-like behaviors following CO2 inhalation. The rodent model of SPS simulates intense trauma that leads to PTSD-like behaviors. Importantly, our recent data has shown significant potentiation of CO2-evoked responses, microglial activation and TDAG8 up-regulation in mice exposed to SPS. The objective of this proposal is to delineate the mechanistic link between microglial acid sensing and inflammation with panic and PTSD responses following trauma. Relevance of microglial mechanisms in panic-PTSD model will be investigated under three specific aims. Aim 1 will test the hypothesis that SPS exposure will exacerbate behavioral, cardiovascular and respiratory responses to CO2 inhalation, a panic inducer. Aim 2 will test the hypothesis that increased CO2-evoked fear and cardiovascular responses following SPS exposure are dependent on microglial acid sensing TDAG8. Aim 3 will test the hypothesis that microglial activation and pro-inflammatory cytokine IL-1? is necessary for CO2-evoked panic responses following SPS. Collectively, our data will determine the physiologic relevance of microglial acid sensor TDAG8 and inflammation in panic comorbid with PTSD. Relevance: Microglial inflammatory mechanisms may provide important leads on how exposure to traumatic stress can lead to panic pathophysiology. This association is critical to the pathophysiology of panic comorbid with PTSD in veterans and may lead to more specific and effective therapies.